Impacts of aging and amyloid-β deposition on plasminogen activators and plasminogen activator inhibitor-1 in the Tg2576 mouse model of Alzheimer's disease.

Abstract

Plasminogen activators (PAs), which convert plasminogen into the fibrinolytic protease plasmin, may initiate the degradation of amyloid-β (Aβ) to suppress the amyloid pathogenesis. In that way, tissue plasminogen activator (tPA)-mediated plasmin activation could maintain a low level of Aβ deposition to delay the pathogenesis of Alzheimer's disease (AD). In a previous study, we reported that tPA/plasmin proteolytic activity is attenuated throughout the brain during aging or with Aβ accumulation but clustered intense around the amyloid plaques in AD brain. The present study demonstrates that the altered proteolytic activity primarily results from the competition between the expressions of tPA and plasminogen activator inhibitor-1 (PAI-1) in the brains of Tg2576 Aβ-transgenic mice, as revealed by immunohistochemistry and immunoblot assays. Compared with that in the brains of younger Tg2576 mice, tPA protein is generally reduced throughout the brain in older Tg2576 mice but elevated near amyloid plaques. In contrary, PAI-1 expression increases during aging or Aβ deposition with its clusters surrounding amyloid plaques. No significant alteration in the expression of urokinase plasminogen activator (uPA) is detected. These results suggest reciprocal feedback influences between tPA, PAI-1 and Aβ during aging and amyloid pathogenesis in AD brain; tPA-mediated plasmin activity is declined throughout the brain causing Aβ deposition during aging, and the Aβ deposits locally attract the cluster of tPA and/or PAI-1 around their deposits to competitively determine tPA/plasmin-mediated Aβ proteolysis.

• Authors: Shin Bi Oh, Nayoung Suh, Inki Kim, Joo-Yong Lee
• Journal: Brain research (Brain Res) Vol. 1597 Pg. 159-67 (Feb 09 2015) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 25454795 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 Elsevier B.V. All rights reserved.

Chemical References

• APP protein, human
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Serpin E2
• Serpine2 protein, mouse
• Tissue Plasminogen Activator
• Fibrinolysin
• Urokinase-Type Plasminogen Activator

Topics

• Aging (metabolism)
• Alzheimer Disease (metabolism, pathology)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics, metabolism)
• Animals
• Cerebral Cortex (metabolism, pathology)
• Disease Models, Animal
• Female
• Fibrinolysin (metabolism)
• Hippocampus (metabolism, pathology)
• Humans
• Mice, Inbred C57BL
• Mice, Transgenic
• Neuroglia (metabolism, pathology)
• Neurons (metabolism, pathology)
• Plaque, Amyloid (metabolism, pathology)
• Serpin E2 (metabolism)
• Tissue Plasminogen Activator (metabolism)
• Urokinase-Type Plasminogen Activator (metabolism)